Crystalline forms of a2a receptor antagonist, preparation methods, and uses thereof

Abstract

Disclosed are crystalline forms of the A2A receptor antagonist 2-(3-cyanophenyl)- 3-(2,6-dimethylpyridin-4-yl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl] pyrazolo[1,5- a]pyrimidine-5-carboxamide, and preparation methods and uses thereof.

Description

[0001] CRYSTALLINE FORMS OF A2A RECEPTOR ANTAGONIST, PREPARATION METHODS, AND USES THEREOF

[0002] TECHNICAL FIELD

[0003] The present invention relates to the field of drugs, and specifically relates to crystalline forms of an A2a receptor antagonist, and preparation methods and uses thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] A number of immunosuppressive pathways are active in the tumour microenvironment which enable tumour cells to evade elimination by cytotoxic T cells and can diminish the clinical response of patients to immunotherapy with anti-checkpoint antibodies. However, only 20-30% of patients respond to checkpoint blockade and the side effects of such treatments are significant (Sukari et al, 2016). Consequently, other approaches to enhance the cytotoxic potential of the tumour microenvironment are actively being investigated. This includes agents that could be used as monotherapies or, more likely, used in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.

[0006] One approach that has attracted attention is to interfere with the production and / or action of adenosine in the tumour microenvironment (Vijayan et al, 2017). Adenosine has immunosuppressive properties and is present in the tumour microenvironment at high concentrations. Adenosine regulates cell function via occupancy of specific GPCRs on the cell surface of the Pl purinoceptor subtypes. The Pl receptor family is further subdivided into Al, A2a, A2b and A3. A2 receptors are subdivided into A2a and A2b, based on high and low affinity for adenosine, respectively. A2a is expressed by lymphocytes and activation of A2a leads to suppression of cytokine production and other effector functions. Recent studies have prompted the development of selective A2a receptor antagonists for use in cancer immunotherapy.

[0007] International patent application publication WO2021 / 224636 (incorporated by reference herein in its entirety) disclosed a series of compounds as A2a receptor antagonists. One of the compounds described is 2-(3-cyanophenyl)-3-(2,6- dimethylpyridin-4-yl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl] pyrazolo[l,5- a]pyrimidine-5-carboxamide (hereinafter referred to as "compound of Formula (I)”):

[0008] The compound of Formula (I) is an orally bioavailable small molecule selective A2a receptor antagonist. In vitro, it enhanced T cell activation and cytokine secretion in primary CD4+ and CD8+ T cells. In vivo, it potentiated anti-tumor response to radiation therapy in combination with anti-PD-1 in 3 different mouse tumor models (CT-26, B 16F 10, and EG7 -OVA) resulting in enhanced tumor growth inhibition, tumor regression, and increased survival compared to monotherapy with either agent or the combination.

[0009] It is known that a crystalline form of a compound can improve the thermodynamic stability, and has the technological operation advantage of easy further purification, easy filtration, drying and so on. Some crystalline forms provide advantages of stability, ease of manufacture and / or formulating. Therefore, it is necessary to further research and develop crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)- 3- hydroxy-3 -methylbutan-2-yl]pyrazolo[l, 5 -a]pyrimidine-5 -carboxamide, which possess characteristics such as high melting point and better stability, suitable for drug formulations.

[0010] BRIEF SUMMARY

[0011] Described herein are crystalline forms of 2-(3-cyanophenyl)-3-(2,6- dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide and methods of use thereof. Also described are crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide as pharmaceutical compositions for use as A2A receptor antagonists.

[0012] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form A. In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin- 4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5- carboxamide is Form B.

[0013] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form C.

[0014] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form D.

[0015] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form E.

[0016] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form F.

[0017] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form G.

[0018] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form H.

[0019] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form I.

[0020] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form J.

[0021] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form K.

[0022] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form L. In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form M.

[0023] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form N.

[0024] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form O.

[0025] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form P.

[0026] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form Q.

[0027] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form R.

[0028] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form S.

[0029] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form T.

[0030] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form U.

[0031] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form V.

[0032] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form W. In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form X.

[0033] In some embodiments crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form Y.

[0034] BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The foregoing and other objects, aspects, features, and advantages of exemplary embodiments will become more apparent and may be better understood by referring to the following description taken in conjunction with the accompanying drawings.

[0036] FIG. 1 illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form A of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0037] FIG. 2 illustrates the differential scanning calorimetry (DSC) curve of crystalline Form A of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0038] FIG. 3 illustrates the thermogravimetric analysis (TGA) curve of crystalline Form A of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0039] FIG. 4 illustrates the 1H-NMR of crystalline Form A of 2-(3-cyanophenyl)-3-(2,6- dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide .

[0040] FIG. 5 illustrates the X-ray powder diffraction pattern (XRPD) of crystalline Form C of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0041] FIG. 6 depicts the unit cell of crystalline Form C of 2-(3-cyanophenyl)-3-(2,6- dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide .

[0042] FIG. 7A illustrates the thermogravimetric analysis (TGA) curve of crystalline Form C of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0043] FIG. 7B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form C of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0044] FIG. 8 illustrates the DVS isotherm plot of crystalline Form C of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0045] FIG. 9 illustrates the X-ray powder diffraction curve of crystalline Form G of 2- (3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0046] FIG. 10A illustrates the differential scanning calorimetry (DSC) curve of crystalline Form G of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0047] FIG. 10B illustrates the TGA curve crystalline Form G of 2-(3-cyanophenyl)-3- (2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide .

[0048] FIG. 11 illustrates the sorption isotherm of crystalline Form G of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0049] FIG. 12 depicts the crystal structure of crystalline Form G of 2-(3-cyanophenyl)- 3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide ; water molecules are depicted in spacefilled style for better visibility.

[0050] FIG. 13 illustrates the XRPD overlay of the samples obtained from VT-XRPD experiments on crystalline Form G of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0051] FIG. 14 illustrates the differential scanning calorimetry (DSC) curve of crystalline Form N of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0052] FIG. 15 illustrates the X-ray powder diffraction pattern of crystalline Form N of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0053] FIG. 16 illustrates the PLM image of Form C crystallized from the crystallization process in 2-methyltetrahydrofuran / heptane.

[0054] FIG. 17A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form B of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0055] FIG. 17B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form B of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0056] FIG. 17C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form B of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0057] FIG. 18A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form D of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0058] FIG. 18B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form D of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0059] FIG. 18C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form D of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0060] FIG. 19A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form E of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0061] FIG. 19B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form E of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0062] FIG. 19C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form E of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0063] FIG. 20A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form F of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0064] FIG. 20B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form F of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0065] FIG. 20C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form F of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0066] FIG. 21 A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form H of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0067] FIG. 2 IB illustrates the differential scanning calorimetry (DSC) curve of crystalline Form H of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0068] FIG. 21C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form H of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0069] FIG. 22A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form I of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0070] FIG. 22B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form I of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0071] FIG. 22C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form I of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0072] FIG. 23A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form J of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0073] FIG. 23B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form J of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0074] FIG. 23C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form J of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0075] FIG. 24A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form K of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0076] FIG. 24B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form K of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0077] FIG. 24C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form K of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0078] FIG. 25A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form L of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0079] FIG. 25B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form L of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0080] FIG. 25C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form L of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0081] FIG. 26 illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form M of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0082] FIG. 27 illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form O of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0083] FIG. 28 illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form P of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0084] FIG. 29A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form Q of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0085] FIG. 29B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form Q of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0086] FIG. 29C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form Q of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0087] FIG. 30A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form R of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0088] FIG. 30B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form R of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0089] FIG. 30C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form R of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0090] FIG. 31 A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form S of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0091] FIG. 3 IB illustrates the differential scanning calorimetry (DSC) curve of crystalline Form S of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0092] FIG. 31C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form S of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0093] FIG. 32A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form T of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0094] FIG. 32B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form T of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0095] FIG. 32C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form T of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0096] FIG. 33A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form U of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0097] FIG. 33B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form U of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0098] FIG. 33C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form U of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0099] FIG. 34A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form V of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0100] FIG. 34B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form V of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0101] FIG. 34C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form V of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0102] FIG. 35A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form W of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0103] FIG. 35B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form W of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0104] FIG. 35C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form W of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0105] FIG. 36A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form X of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0106] FIG. 36B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form X of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0107] FIG. 36C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form X of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide.

[0108] FIG. 37 illustrates an XRD overlay of simulated SXRD data from Form C of 2- (3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide (bottom plot) and Form Y of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide (top plot).

[0109] DETAILED DESCRIPTION

[0110] The disclosed pharmaceutical compositions and methods may be understood more readily by reference to the following detailed description, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

[0111] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

[0112] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein.

[0113] Definitions

[0114] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0115] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0116] As used herein, the term “about” preceding a numerical value or a series of numerical values means ±10% of the numerical value unless otherwise indicated. For example, “about 100 mg” means 90 to 110 mg.

[0117] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the invention.

[0118] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”.

[0119] When used herein “consisting of’ excludes any element, step, or ingredient not specified in the claim element. When used herein, “consisting essentially of’ does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the aforementioned terms of “comprising”, “containing”, “including”, and “having”, whenever used herein in the context of an aspect or embodiment of the invention can be replaced with the term “consisting of’ or “consisting essentially of’ to vary scopes of the disclosure.

[0120] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or”, a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0121] As used herein, “treatment” or “treat” refers to the treatment of a disease, disorder, or medical condition (such as a gastrointestinal inflammatory disease), in a patient, such as a mammal (particularly a human) which includes one or more of the following:

[0122] (a) preventing the disease, disorder, or medical condition from occurring, i.e., preventing the reoccurrence of the disease or medical condition or prophylactic treatment of a patient that is pre-disposed to the disease or medical condition;

[0123] (b) ameliorating the disease, disorder, or medical condition, i.e., eliminating or causing regression of the disease, disorder, or medical condition in a patient, including counteracting the effects of other therapeutic agents;

[0124] (c) suppressing the disease, disorder, or medical condition, i.e., slowing or arresting the development of the disease, disorder, or medical condition in a patient; or

[0125] (d) alleviating the symptoms of the disease, disorder, or medical condition in a patient.

[0126] The terms “efficacy” and “effective” as used herein in the context of a dose, dosage regimen, treatment or method refer to the effectiveness of a particular dose, dosage or treatment regimen. Efficacy can be measured based on change in the course of the disease in response to an agent of the present invention. For example, 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide can be administered to a subject in an amount and for a time sufficient to induce an improvement, preferably a sustained improvement, in at least one indicator that reflects the severity of the disorder that is being treated. Various indicators that reflect the extent of the subject's illness, disease or condition can be assessed for determining whether the amount and time of the treatment is sufficient. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the disorder in question. The degree of improvement generally is determined by a physician, who can make this determination based on signs, symptoms, biopsies, or other test results, and who can also employ questionnaires that are administered to the subject, such as quality-of-life questionnaires developed for a given disease.

[0127] The term “an effective amount” means an amount sufficient to affect treatment when administered to a patient in need of treatment.

[0128] The term “subject” includes any human or nonhuman animal, “non-human animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” can be used interchangeably herein.

[0129] The term “X-ray powder diffraction” or “XRPD” used in the present invention refers to an X-ray powder diffraction pattern that is obtained according to the Bragg formula: 2d sin 0 = nZ (where X is the wavelength of the X-ray, Z= 1 .54056 A, the order of diffraction n is any positive integer, generally taking the first-order diffraction peak, n=l), when the X-ray is incident on a certain atomic plane of a crystal or a partial crystal sample having a d-lattice plane spacing at a glancing angle 0 (the complementary angle of incidence angle, also called the Bragg angle), the Bragg equation can be satisfied.

[0130] For crystalline forms described herein, the peaks of the XRPD pattern can be obtained from the pattern by conventional methods, which are known to those skilled in the field. Referring to a Form, such as Form A, Form B, etc. throughout refers to a polymorphic form of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- |(25>)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide.

[0131] The term “substantially pure” is used herein to describe a crystalline form that has a purity in crystalline structure or form (such as, for example Form A substantial pure of Form S) of greater than 90%, greater than 96% pure, greater than 97% pure, greater than 98% pure, or greater than 99% pure.

[0132] The term “20 or 20 angle” used in the present invention refers to the diffraction angle, 0 is the Bragg angle, and the unit of which is ° or degree. The error range of 20 is from ±0.1 to ±0.5, preferably from ±0.1 to ±0.3, and more preferably ±0.2.

[0133] The term “interplanar spacing or interplanar distance (d value)” used in the present invention means that the space lattice selects three unit vectors a, b, c, wherein the each of the them connects two adjacent lattice dots, and the three vectors divide the lattice into juxtaposed parallel juxtagonal units, called the interplanar spacing. The space lattice is divided according to the determined parallelepiped unit lines to obtain a set of linear grids, which is called a space lattice or a lattice. The lattice reflects the periodicity of the crystal structure with geometric points and lines. Different crystal planes have different interplanar spacings (i.e., distance between two adjacent parallel crystal planes); the unit is A or angstrom.

[0134] The term “differential scanning calorimetry” or “DSC” used in the present invention means to measure the temperature difference and heat flow difference between the sample and the reference during the heating or constant temperature process of the sample, to characterize all physical and chemical changes associated with the thermal effect, and to obtain phase change information of the sample.

[0135] The term “thermogravimetric analysis” or “TGA” used in the present invention means to measure the thermal stability of a sample, in which changes in the weight of a sample are measured while its temperature is increased. Moisture and volatile contents of a sample can be measured by TGA. This measurement provides information about physical phenomena, such as phase transitions, absorption, adsorption and desorption; as well as chemical phenomena including chemisorptions, thermal decomposition, and solid-gas reactions (e.g., oxidation or reduction).

[0136] Crystalline Forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide

[0137] 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide refers to the compound having the structure:

[0138]

[0139] Formula (I)

[0140] Form A

[0141] According to embodiments of the invention, crystalline Form A is a non- stoichiometric channel hydrate that shows a slightly different XRPD pattern as a function of its water content. In some embodiments, crystalline Form A contains about 1.6% water content.

[0142] Form A of 2-(3-cyanophenyI)-3-(2,6-dimethyIpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methyIbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide is characterized as having:

[0143] (a) an X-ray powder diffraction pattern, wherein the X-ray powder diffraction pattern comprises substantially the same peaks at diffraction angles (20) as shown in FIG. 1 ;

[0144] (b) an X-ray diffraction pattern with characteristic peaks at 6.03+0.1° 20, 8.22+0.1 °20, 12.04+0.1 °20, 13.11+0.1 °20, 16.73+0.1 °20, 17.63 +0.1 °20, 18.75 +0.1 °20, 24.14 +0.1 °20, 25.10 +0.1 °20 and 27.61 +0.1 °20;

[0145] (c) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting peak at Tonset of about 120.2°C and a recrystallization peak at TonSet of about, 133 ,5°C, and a melting peak at TonSet of about 191.5°C with an enthalpy of about 75 J / g;

[0146] (d) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting endothermic peak of from 190 °C to 200 °C, preferably from 190°C to 195°C, and more preferably about 193.6°C;

[0147] (e) a differential scanning calorimetry curve substantially similar to FIG. 2;

[0148] (f) a thermogravimetric analysis curve substantially similar to FIG. 3; (g) a thermogravimetric analysis curve shows about 0.3% weight loss at about 120.0°C;

[0149] (h) or combinations thereof.

[0150] In some embodiments, Form A is characterized as having at least two, at least three, at least four, at least five, at least six or all seven of the properties selected from (a) to (g). In Some embodiments. Form A is characterized as having properties (a), (b), (c), (d), (e), (f) and (g). In some embodiments, Form A is characterized as having property (a), (b), (c), (d), and (g) or combinations thereof. In some embodiments, Form A is characterized as having the properties (a), (e), and (f). In some embodiments, Form A is characterized as having one, two or three of properties (b), (d), and (g).

[0151] In some embodiments, Form A is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1. In some embodiments, Form A is characterized as having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.03+0.1° 20, 8.22+0.1 °20, 12.04+0.1 °20, 13.11+0.1 °20, 16.73+0.1 °20, 17.63 +0.1 °20, 18.75 +0.1 °20, 24.14 +0.1 °20, 25.10 +0.1 °20 and 27.61 +0.1 °20.

[0152] In some embodiments, crystalline Form A is a metastable form.

[0153] In certain embodiments, crystalline Form A can convert to crystalline Form C in an organic solvent at 25°C and 50°C. Examples of the organic solvent include, but not limited to, ethanol, acetone, t-butyl methyl ester, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, and heptane.

[0154] In some embodiments Form A is substantially free of Form S. In some embodiments Form A is greater than 95% pure, greater than 96% pure, greater than 97% pure, greater than 98% pure, or greater than 99% pure.

[0155] Form S

[0156] In one general aspect, the invention relates to crystalline Form S of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide. Form S can be obtained from storing Form A at ambient condition for about 2 months or exposure of Form A to 92%RH for 1 day. DSC of Form S shows a dehydration peak at Tonset of 14.3°C with an enthalpy of about 33J / g, and a melting peak at Tonset of 120.6°C and a recrystallization peak at Tonset of 133.1°C. Then it melts at Tonset of 190.9°C with an enthalpy of about 80J / g.

[0157] In some embodiments of the invention crystalline Form S of 2-(3-cyanophenyl)- 3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide is characterized as having:

[0158] (a) an X-ray powder diffraction pattern, wherein the X-ray powder diffraction pattern comprises substantially the same peaks at diffraction angles (20) as shown in FIG. 31 A;

[0159] (b) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a dehydration peak at Tonset of 14.3°C with an enthalpy of about 33J / g, and a melting peak at Tonset of 120.6°C and a recrystallization peak at Tonset of 133.1°C. Then it melts at Tonset of 190.9°C with an enthalpy of about 80J / g;

[0160] (c) a differential scanning calorimetry curve substantially similar to FIG. 3 IB;

[0161] (d) or combinations thereof.

[0162] In some embodiments, Form S is characterized as having at least two, or at least three of the properties selected from (a) to (c). In Some embodiments Form S is characterized as having properties (a), (b) and (c). In some embodiments, Form S is characterized as having at least two of the properties selected from (a), (b) and (c). In some embodiments. Form S is characterized as having each of the properties (a), (b) and (c). In some embodiments, crystalline Form S is a hydrate.

[0163] Form C

[0164] In one general aspect, the invention relates to crystalline Form C of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0165] According to embodiments of the invention, crystalline Form C is an anhydrate.

[0166] In some embodiments, Form C is characterized as having:

[0167] (a) an X-ray powder diffraction pattern, wherein the X-ray powder diffraction pattern comprises substantially the same peaks at diffraction angles (20) as shown in FIG. 5;. (b) an X-ray diffraction pattern with characteristic peaks at 3.12+0.1° 20, 6.19+0.1 °20, 9.26+0.1 °20, 12.35 +0.1 °20, 13.28+0.1 °20, 14.16 +0.1 °20 , 15.44 +0.1 °20 , 16.40 +0.1 °20 , 17.71 +0.1 °20 and 18.55 +0.1 °20;.

[0168] (c) unit cell dimensions comprising a=l 1.25010(2)A, b=7.56347(13)A, c=28.8641(3)A, alpha=90 deg., beta=94.6337(ll) deg., gamma=90 deg;

[0169] (d) unit cell dimensions are substantially similar to those in Table 23.

[0170] (e) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting peak at Tonset of about 191.2°C with an enthalpy of about 71 J / g;

[0171] (f) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C, preferably from 190°C to 195°C, and more preferably about

[0172] 192.6°C;

[0173] (g) a differential scanning calorimetry curve is substantially similar to the differential scanning calorimetry curve in FIG. 7B ;

[0174] (h) a thermogravimetric analysis curve, wherein the thermogravimetric analysis curve is substantially similar to the thermogravimetric analysis curve in FIG. 7A.

[0175] (i) thermogravimetric analysis curve shows about 0.6% weight loss at about 200.0°C;

[0176] (j) substantially the same X-ray diffraction (XRPD) pattern post storage at 40°C and 75% RH for at least 4 weeks;

[0177] (k) substantially the same X-ray diffraction (XRPD) pattern post storage at 25 °C and 92% RH for at least 4 weeks;

[0178] (l) or combinations thereof.

[0179] In some embodiments, Form C is characterized as having at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, nine, ten or all eleven of the properties selected from (a) to (k). In Some embodiments Form C is characterized as having properties (a), (b), (c), (e), (f), and (i). In other embodiments Form C is characterized as having properties one, two, or three of the properties (b), (f) and (i).

[0180] In other embodiments Form C is characterized as having properties (a), (d),(e) and (h).

[0181] In some embodiments, crystalline Form C is a thermodynamically stable anhydrate. In certain embodiments, crystalline Form C is stable in a.w. < 0.4 at 25°C, and it converts to crystalline Form G in a.w. > 0.6 at 25°C.

[0182] Form G

[0183] In one general aspect, the invention relates to crystalline Form G of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide. According to embodiments of the invention, crystalline Form G is a dihydrate.

[0184] In some embodiments, Form G is characterized as having:

[0185] (a) an X-ray powder diffraction pattern, wherein the X-ray powder diffraction pattern comprises substantially the same peaks at diffraction angles (20) as shown in FIG. 9;

[0186] (b) an X-ray diffraction pattern with characteristic peaks at 5.55 ±0.1° 20, 8.22 ±0.1 °20, 9.49 ±0.1 °20, 12.53 ±0.1 °20, 13.41 ±0.1 °20, 13.53 ±0.1 °20 , 14.46 ±0.1 °20 , 14.72 ±0.1 °20 , 15.48 ±0.1 °20, 16.65 ±0.1 °20 , 17.57 ±0.1 °20, 18.24 ±0.1 °20, 18.50 ±0.1 °20, 20.07 ±0.1 °20 , 20.51 ±0.1 °20, 21.44 ±0.1 °20, 22.68 ±0.1 °20, 24.52 ±0.1 °20, and 25.90 ±0.1 °20.

[0187] (c) unit cell dimensions comprising a=7.1582(2)A, b=11.3672(3)A, c=32.0153(7)A, alpha=90 deg., beta=90 deg., gamma=90 deg;

[0188] (d) unit cell dimensions are substantially similar to those in Table 2.

[0189] (e) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a dehydration peak at TonSet of 33.3°C with an enthalpy of about 206 J / g and an exothermic peak at TonSet of 168.1°C with an enthalpy of about 23 J / g, and an endothermic peak at TonSetof 193.7°C with an enthalpy of about 76 J / g.

[0190] (f) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C, preferably from 190°C to 195°C, and more preferably about 194.4°C. (g) differential scanning calorimetry curve is substantially similar to the differential scanning calorimetry curve in FIG. 10A;

[0191] (h) a thermogravimetric analysis curve, wherein the thermogravimetric analysis curve is substantially similar to the thermogravimetric analysis curve in FIG. 10B;

[0192] (i) thermogravimetric analysis curve shows about 6.2% weight loss at about 65°C;

[0193] (j) substantially the same X-ray diffraction (XRPD) pattern post storage at 40°C and 75% RH for at least 4 weeks.

[0194] (k) substantially the same X-ray diffraction (XRPD) pattern post storage at 25 °C and 92% RH for at least 4 weeks; or

[0195] (l) combinations thereof.

[0196] In some embodiments, Form G is characterized as having at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, nine, ten or all eleven of the properties selected from (a) to (k). In Some embodiments Form G is characterized as having properties (a), (b), (c), (e), (f), and (i). In other embodiments Form G is characterized as having properties one, two, or three of the properties (b), (f) and (i). In other embodiments Form G is characterized as having properties (a), (d),(e) and (h).

[0197] In some embodiments, crystalline Form G is stable in a.w. > 0.6 at 25°C.

[0198] FORM N

[0199] In one general aspect, the invention relates to crystalline Form N of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide.

[0200] According to embodiments of the invention, crystalline Form N is an anhydrate.

[0201] In some embodiments, Form N is characterized by

[0202] (a) an X-ray powder diffraction pattern, wherein the X-ray powder diffraction pattern comprises substantially the same peaks at diffraction angles (20) as shown in FIG. 15;

[0203] (b) an X-ray diffraction pattern with characteristic peaks at 5.44 ±0.1° 20, at 6.05 ±0.1° 20, at 8.52 ±0.1° 20, at 13.29 ±0.1° 20, at 14.85 ±0.1° 20, at 16.40 ±0.1° 20, at 16.76 ±0.1° 20, at 18.23 ±0.1° 20, at 24.43 ±0.1° 20, and at 24.95 ±0.1° 20; (c) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises an exothermic peak at Tonset of 164.1°C with an enthalpy of about 23 J / g and an endothermic peak at TonSet of 193.8°C with an enthalpy of about 83 J / g;

[0204] (d) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C, preferably from 190°C to 195°C, and more preferably about 194.3°C;

[0205] (e) differential scanning calorimetry curve is substantially similar to FIG. 14;

[0206] (f) or combinations thereof.

[0207] In some embodiments, Form N is characterized as having at least two, at least three, at least four, or all least five of the properties selected from (a) to (e). In some embodiments Form N is characterized as having one two or three of the properties selected from (a), (b), and (d). In some embodiments, crystalline Form N is metastable. In certain embodiments, crystalline Form N is not stable at ambient condition.

[0208] Methods of Preparing Crystalline Forms

[0209] Crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide are prepared as outlined in the Examples. It is noted that solvents, temperatures and other reaction conditions presented herein may vary.

[0210] Suitable Solvents

[0211] Therapeutic agents that are administrable to mammals, Such as humans, must be prepared by following regulatory guidelines. Such government regulated guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable contamination levels of active therapeutic agents, such as, for example, the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities and consis tent with industrial safety concerns. Categories of Solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Solvents are categorized into three classes. Class 1 sol vents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies. Class 1 solvents, which are to be avoided, include: benzene: carbon tetrachloride; 1 ,2-dichloroethane; 1,1 -di chloroethene; and 1,1,1 -trichloroethane. Examples of Class 2 solvents are: acetonitrile, chloroben Zene, chloroform, cyclohexane, 1,2-dichloroethene, dichlo romethane, 1 ,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxy ethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxy ethanol, methylbutyl ketone, methylcyclohexane, N-meth ylpyrrolidine, nitromethane, pyridine, Sulfolane, tetralin, toluene, 1.1.2-trichloroethene and Xylene. Class 3 solvents, which possess low toxicity, include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-l -propanol, pentane, 1 -pentanol. 1 -propanol, 2- propanol, propyl acetate, and tet rahydrofuran. In some embodiments, compositions comprising 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide include a residual amount of an organic solvent(s). In some embodiments, compositions comprising 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide include a detectable amount of an organic solvent(s). In some embodiments, compositions comprising amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1- butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-l -propanol, pentane, 1 -pentanol. 1-propa nol, 2- propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is ethanol. The methods and compositions described herein include the use of crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide. In addition, the crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents Such as water, ethanol, and the like, include a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl- 1 -butanol, methylethyl ketone, methylisobutyl ketone,

[0212] 2-methyl-l -propanol, pentane, 1 -pentanol. 1 -propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is ethanol. The methods and compositions described herein include the use of crystalline forms of 2-(3-cyanophenyl)-

[0213] 3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide. In addition, the crystalline forms of 2-(3-cyanophenyl)-3- (2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents Such as water, ethanol, and the like.

[0214] According to embodiments of the invention, crystalline forms can be prepared by recrystallization or equilibration with a solvent or a solvent mixture.

[0215] The recrystallization method is not particularly limited, and can be carried out by a conventional recrystallization process. For example, the material, i.e., 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide , can be dissolved in a solvent or a solvent mixture under heating, and then the solution is cooled slowly to precipitate a crystal. After the completion of crystallization, the desired crystal can be obtained via filtering and drying. The crystallization method of the present invention includes room temperature crystallization, cooling crystallization and the like.

[0216] The equilibration method can be carried out in a solvent or a solvent mixture at a room temperature (about 20 -30 °C) or at an elevated temperature (such as 50-80 °C). The compound of Formula (I) and the solvent or solvent mixture are mixed to forma a suspension, and the suspension is allowed to stir for a suitable amount of time to obtain the desired crystalline form.

[0217] Examples of the solvent that can be used in the recrystallization or the equilibration include, but not limited to, water, methanol, ethanol, isopropyl acetate, acetone, t-butyl methyl ether, tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate, methyl ethyl ketone, toluene, 2-propanol, heptane, heptane, 1,4-dioxnae, or any combinations thereof.

[0218] The starting material used in the methods for preparing the crystalline forms of the present invention can be 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)- 3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide in any form, and the specific forms include, but are not limited to, amorphous form, arbitrary crystal forms and the like.

[0219] In some embodiments, the invention presents a method of preparing crystalline Form A.

[0220] In some embodiments, the method of preparing crystalline Form A comprises recrystallizing 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .

[0221] In certain embodiments, the method comprises dissolving 2-(3-cyanophenyl)-3- (2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide in acetonitrile or a mixture of acetonitrile and water to form a solution under heating, preferably under refluxing, and then cooling the solution to obtain crystalline Form A.

[0222] In some embodiments, the invention presents a method of preparing crystalline Form C. In some embodiments, the method of preparing crystalline Form C comprises suspending 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide in ethyl acetate to form a suspension, optionally adding a Form C seed, and stirring the suspension at a suitable temperature for a suitable period of time to obtain crystalline Form C.

[0223] In certain embodiments, the ratio of the volume (ml) of ethyl acetate to the weight (gram) of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy- 3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide is about 2 to 10, preferably about 4-6, more preferably about 5.

[0224] In certain embodiments, the suitable temperature is about 30-70 °C, preferably about 40-60 °C, more preferably about 50 °C.

[0225] In certain embodiments, the suitable period of time is about 1-5 days, preferably about 2-4 days, more preferably about 3 days.

[0226] In some embodiments, the method of preparing crystalline Form C comprises dissolving 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide in 2- methyltetrahydrofuran to form a solution under heating, cooling the solution to a suitable temperature, adding heptane, and obtaining crystalline Form C.

[0227] In certain embodiments, the ratio of the volume (ml) of the 2- methyltetrahydrofuran to the weight (gram) of 2-(3-cyanophenyl)-3-(2,6- dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide is about 3 to 11, preferably about 5 to 9, more preferably about 7.

[0228] In certain embodiments, the solution is formed at a temperature of about 45- 85 °C, preferably about 55-75 °C, more preferably about 65 °C.

[0229] In certain embodiments, the suitable temperature is about 10 to 30 °C, preferably about 15 to 25 °C, more preferably about 20 °C.

[0230] In certain embodiments, the ratio of the volume (ml) of the added heptane to the weight (gram) of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy- 3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide is about 4 to 12, preferably about 6 to 10, more preferably about 8.

[0231] In certain embodiments, the method comprises optionally adding a Form C seed when the solution is cooled to a temperature of about 50 to 60 °C, preferably about 55 °C.

[0232] In some embodiments, the invention presents a method of preparing crystalline Form G.

[0233] In some embodiments, the method of preparing crystalline Form G comprises suspending 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide in a mixture of acetone and water to form a suspension, optionally adding a Form G seed, and stirring the suspension at a suitable temperature for a suitable period of time to obtain crystalline Form G.

[0234] In certain embodiments, the volume ratio of acetone to water is about 0.5 to 2, preferably about 1.

[0235] In certain embodiments, the ratio of the volume (ml) of the mixture of acetone and water to the weight (gram) of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide is about 2 to 10, preferably about 4-6, more preferably about 5.

[0236] In certain embodiments, the suitable temperature is about 20-40 °C, preferably about 20-30 °C, more preferably about 25 °C.

[0237] In certain embodiments, the suitable period of time is about 2-10 days, preferably about 4-6 days, more preferably about 5 days.

[0238] In some embodiments, the invention presents a method of preparing crystalline Form N.

[0239] In some embodiments, the method of preparing crystalline Form N comprises heating crystalline Form G of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .

[0240] Pharmaceutical Compositions In one another general aspect, the invention presents a pharmaceutical composition comprising an effective amount of, in particular a therapeutically effective amount of, at least one of the crystalline forms described herein, and a pharmaceutically acceptable carrier.

[0241] As used herein, the term “carrier” refers to any excipient, diluent, buffer, stabilizer, or other material well known in the art for pharmaceutical formulations. Pharmaceutically acceptable carriers in particular are non-toxic and should not interfere with the efficacy of the active ingredient. The pharmaceutically acceptable carriers include excipients and / or additives suitable for use in the pharmaceutical compositions known in the art, e.g., as listed in “Remington: The Science & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995), and in the “Physician's Desk Reference”, 52nd ed., Medical Economics, Montvale, N.J. (1998), the disclosures of which are entirely incorporated herein by reference. Any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention.

[0242] The choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, the carriers or excipients used in the pharmaceutical compositions of this invention are commercially- available. By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999).

[0243] Representative examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical compositions.

[0244] The pharmaceutical compositions of the disclosure are preferably packaged in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for dosing a patient, i.e., each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units. For example, such unit dosage forms may be capsules, tablets, pills, and the like, or unit packages suitable for parenteral administration.

[0245] The pharmaceutical composition disclosed herein can be administrated via oral, inhalation, rectal, parenteral or topical administration to a subject in need thereof. For oral administration, the pharmaceutical composition may be a regular solid formulation such as tablets, powder, granule, capsules and the like, a liquid formulation such as water or oil suspension or other liquid formulation such as syrup, solution, suspension or the like; for parenteral administration, the pharmaceutical composition may be solution, water solution, oil suspension concentrate, lyophilized powder or the like. Preferably, the formulation of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule. The pharmaceutical composition can be a single unit administration with an accurate dosage. In addition, the pharmaceutical composition may further comprise additional active ingredients.

[0246] All formulations of the pharmaceutical composition disclosed herein can be produced by the conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients, then to make the desired formulation.

[0247] Methods of Use

[0248] In one another general aspect, the invention presents the uses of crystalline forms or the pharmaceutical compositions of the invention, particularly the uses as A2a receptor antagonists.

[0249] In one embodiment, the invention presents a method of treating a disease or disorder in which A2a is implicated, comprising administering to a subject in need thereof an effective amount of crystalline form or the pharmaceutical composition described herein.

[0250] In one embodiment, the invention presents a use of crystalline form or the pharmaceutical composition in the preparation of a medicament for the treatment of a disease or disorder.

[0251] In certain embodiments, the disease or disorder is one in which A2a receptor activity is implicated.

[0252] In certain embodiments, the disease or disorder is cancer, particularly solid tumors such as lung cancer.

[0253] In certain embodiments, the lung cancer is non-small cell lung cancer.

[0254] Examples

[0255] The following specific examples are used to further describe the particular aspects of the invention, but these examples are not intended to limit the scope of the invention in any way.

[0256] List of Abbreviations:

[0257] SM Starting Material

[0258] DP Desired Product

[0259] XRPD X-Ray Powder Diffraction

[0260] DSC Differential Scanning Calorimetry

[0261] TGA Thermogravimetric Analysis

[0262] AcOH Acetic acid

[0263] DIPEA / DIEA N, N-Diisopropylethylamine

[0264] DMF N, N-Dimethylformamide

[0265] DMP Dess-Martin periodinane

[0266] EDO l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EEDQ 2-Ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline

[0267] Et2O Ethyl Ether

[0268] EtOAc or EA Ethyl acetate

[0269] EtOH Ethanol

[0270] HATU O-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0271] HOBt 1 -Hydroxybenzotriazole

[0272] IMS Industrial Methylated Spirit

[0273] IPAc Isopropyl acetate

[0274] MeCN / ACN Acetonitrile

[0275] MeOH Methanol

[0276] 2-Me-THF 2-Methyltetrahydrofuran

[0277] MMAE Monomethyl auristatin E

[0278] MTBE Methyl tert-butyl ether

[0279] NBS N-Bromosuccinimide

[0280] PTSA p-Toluenesulfonic acid

[0281] Prep-HPLC Preparative high performance liquid chromatography

[0282] TEA Triethyl amine

[0283] TFA Trifluoroacetic acid

[0284] THF Tetrahydrofuran

[0285] MTBE Methyl Tert-Butyl Ether

[0286] IPAc Isopropyl Acetate

[0287] Example 1: Preparation of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)-

[0288] N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide

[0289] 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide was prepared according to Scheme 1:

[0290]

[0291] Scheme 1

[0292] Step 1 - Cyclisation

[0293] A solution of diethyl acetylenedicarboxylate (119.66 mL, 747.5mmol) in IMS (50 mL) was added drop-wise over 20 mins to a stirred solution of 3-(5-amino- lH-pyrazol-3-yl)benzonitrile (98.35 g, 533.93mmol) and acetic acid (152.82 mL, 2669.7mmol) in IMS (1475mL), during which time there was slight warming to an internal temperature of 35 °C and a precipitate began to form. The resulting mixture was then stirred at room temperature for 64 hours after which time UPLCMS analysis showed complete consumption of SM (starting material) and formation of the DP (desired product). The suspension was cooled in an ice bath, filtered and the collected solids washed with IMS (2 x 500 mL), Et2O (3 x 500 mL) and vacuum dried to afford ethyl 2-(3-cyanophenyl)-7- hydroxy- pyrazolo[l,5-a]pyrimidine-5-carboxylate (131g, 424.92 mmol, 80% yield) as a cream solid.

[0294] LC-MS: m / z 309.1 = [M+H]+

[0295] JH NMR (500 MHz, DMSO) 5 13.11 (br s, 1H), 8.44 (br t,J= 1.5 Hz, 1H), 8.35 (br dt, J= 8.0, 1.5 Hz, 1H), 7.90 (br dt, J= 7.6, 1.5 Hz, 1H), 7.70 (apr t, J= 7.8 Hz, 1H), 6.85 (s, 1H), 6.33 (s, 1H), 4.42 (q, J= 7.1 Hz, 2H), 1.37 (t,J= 7.1 Hz, 3H).

[0296] Step 2 - Chlorination Ethyl 2-(3-cyanophenyl)-7-hydroxy-pyrazolo[l,5-a]pyrimidine-5-carboxylate (131.0 g, 424.92mmol) was suspended in POCh (619.91 mL, 8498.5mmol) and the resulting mixture was stirred at gentle reflux at 110 °C for 5 hours after which time UPLCMS analysis showed consumption of starting material SM and formation of the DP. The mixture was allowed to cool before being concentrated in vacuo at 45 °C. The resulting residue was azeotroped with toluene (3 x 600 mL) to afford an orange residue. The flask was placed in an ice bath and chilled MeOH (600 mL) was added cautiously. After addition of the solvent, the mixture was stirred for 20 minutes at room temperature before the solid was collected by filtration. The solid was thoroughly washed with MeOH (4 x 400mL) before being dried to afford ethyl 7-chloro-2-(3- cyanophenyl)pyrazolo[l,5-a]pyrimidine-5-carboxylate (128g,391.75mmol, 92% yield) as a yellow solid.

[0297] LC-MS : m / z 327.0 / 329.0 = [M+H]+

[0298] ' H NMR (500 MHz, DMSO-76) 58.55 (t,J= 1.8 Hz, 1H), 8.45 (td, 7= 7.8, 1.8 Hz, 1H), 7.96 (td, J= 7.8, 1.8 Hz, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.77 (t,7= 7.8 Hz, 1H), 4.42 (q, J= 7.1 Hz, 2H), 1.38 (t, J= 7.1 Hz, 3H).

[0299] Step 3- Hydrogenation

[0300] Ethyl 7-chloro-2-(3-cyanophenyl)pyrazolo[l,5-a]pyrimidine-5-carboxylate (53.43 g, 163.52mmol) was placed in a flat-bottomed 3-neck 5L flask equipped with a triangular cross- section rod stirrer bar. Palladium on carbon (10%) (4.35 g, 4.09mmol) was then added, followed by ethyl acetate (3200mL) and triethylamine (113.96 mL, 817.62mmol), and the necks sealed. Under vigorous stirring the flask contents were evacuated and backfilled with nitrogen (3 x cycles), then evacuated and backfilled with hydrogen (5 x cycles) and stirred vigorously at room temperature with two hydrogen balloons fitted. After 75 mins, UPLCMS analysis showed consumption of SM and formation of the DP as an indeterminate mixture of dechlorinated and over reduced product (alongside a possible trace quantity of the bis over- reduced species). The resulting suspension was diluted portion-wise into approx, twice the volume of chloroform (6L) to solubilize the mixture, which was then filtered through a plug of Celite, eluting with chloroform (4 x 500 mL). The combined filtrates were concentrated in vacuo to afford the crude material as a yellow solid (69.4 g). UPLCMS analysis of this material showed only a single peak consisting of a co-eluting mixture of the two products. NMR analysis showed a ~ 5 : 1 ratio of ethyl 2-(3- cyanophenyl)pyrazolo[l,5-a]pyrimidine-5-carboxylate (39.83g, 136.27 mmol, 83% yield) and ethyl 2-(3-cyanophenyl)-4,7-dihydropyrazolo[l,5- a]pyrimidine- 5-carboxylate (8.02g, 27.255mmol, 17% yield) as well as ~ 1 equiv of Et3N.HCl. The material was taken into the subsequent oxidation without further purification. LC-MS: m / z 293.1 / 295.1 = [M+H]+

[0301] Step 4 - Oxidation

[0302] Activated Manganese dioxide (142.18 g, 1635.4mmol) was added to the solution of a crude mixture of ethyl 2-(3-cyanophenyl)pyrazolo[l,5-a]pyrimidine-5- carboxylate and ethyl 2-(3- cyanophenyl)-4,7-dihydropyrazolo[l,5- a]pyrimidine-5-carboxylate (95.71 g, 327.08mmol) in chloroform (3200mL) and the resulting mixture stirred vigorously at room temperature for 3 hours, after which time UPLCMS analysis showed no visible change in the UV trace but complete consumption of the SM and formation of the desired product on manual analysis of the mass data. The mixture was filtered through a plug of Celite, eluting with chloroform (4 x 1000 mL) until the filtrates ran colorless. The combined filtrates were then concentrated in vacuo to approximately 2000 mL. The combined aqueous portions were then washed with chloroform (500 mL) and the combined organic portions were dried over Na2SO4, filtered and concentrated in vacuo to afford crude ethyl 2-(3-cyanophenyl)pyrazolo[l,5- a]pyrimidine-5- carboxylate (92.9g,317.84mmol, 97% yield) [N103-95- 1 ] as a yellow solid.

[0303] LC-MS: m / z 293.1 = [M+H]+

[0304] ' H NMR (500 MHz, DMSCW6) 59.31 (d, J= 7.2 Hz, 1H), 8.51 (t,J= 1.8 Hz, 1H), 8.40 (d, J= 7.8 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.74 (t, J= 7.8 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J= 7.2 Hz, 1H), 4.40 (q, J= 7.1 Hz, 2H), 1.37 (t,J= 7.1 Hz, 3H). Step 5- Bromination

[0305] NBS (67.88 g, 381.4mmol) was added in one-portion to a stirred partial suspension of ethyl 2- (3-cyanophenyl)pyrazolo[l,5-a]pyrimidine-5-carboxylate (92.9 g, 317.84mmol) in DMF (1590mL) after which the solids soon dissolved and the mixture was stirred at room temperature for 60 mins, after which time UPLCMS analysis showed complete consumption of SM and formation of the DP as the sole UV active species. The mixture was cooled in an ice bath before water (3200 mL) was added slowly [NB - moderate exotherm. Maximum internal temperature reached was 35 °C]. The resulting suspension was stirred in the ice bath for 5 mins, then at room temperature for 30 mins before the solid was collected by filtration. The collected solids were washed with water (4 x 800 mL) and vacuum dried to afford ethyl 3-bromo-2-(3-cyanophenyl)pyrazolo[l,5- a]pyrimidine-5-carboxylate (115.2g, 310.35mmol, 98% yield) as a yellow solid.

[0306] LC-MS: m / z 373.1 = [M+H]+

[0307] JH NMR (500 MHz, DMSO) 5 9.40 (d, J= 7.2 Hz, 1H), 8.41 (br t, J= 1.5 Hz, 1H), 8.37 (br dt, J= 8.0, 1.5 Hz, 1H), 8.03 (br dt, J= 7.8, 1.5 Hz, 1H), 7.82 (apr t, J= 7.9 Hz, 1H), 7.67 (d, J= 7.2 Hz, 1H), 4.44 (q, J= 7.1 Hz, 2H), 1.39 (t, J= 7.1 Hz, 3H).

[0308] Step 6 -Suzuki coupling

[0309] A partial suspension of sodium bicarbonate (33.38 g, 397.37mmol) in water (295mL) was added to a solution of ethyl 3-bromo-2-(3-cyanophenyl)pyrazolo [l,5-a]pyrimidine-5-carboxylate (59. g, 158.95mmol) in 1,4-dioxane (1180mL), and the resulting mixture de-oxygenated via nitrogen sparging for 15 mins. Pd(lBu3P)2 (4.06 g, 7.95mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2- yl)pyridine (44.46 g, 190.74mmol) were then added and the contents evacuated and backfilled with nitrogen (3 x cycles). The mixture was then stirred at 50 °C for 3.5 hours after which time UPLCMS analysis showed complete consumption of SM and formation of the DP as the sole UV active species. The mixture was cooled to room temperature, poured into water (3000 mL) and the resulting suspension was stirred vigorously for 10 mins before the solid was collected by filtration. The solids were washed with water (2 x 1500 mL - fully homogenising the suspension each time before re-applying vacuum) and then vacuum dried on the sinter overnight to afford a spongey, pale yellow solid (67.4 g). This material was slurried in MeCN (600 mL) and concentrated in vacuo to azeotrope out the residual water and dioxane, affording a yellow-brown solid (65.6 g). This material was re-dissolved in chloroform (300 mL), activated decolourising charcoal (3 g) added, and the mixture stirred at reflux for 10 mins. The mixture was then cooled to room temperature before being filtered through a plug of Celite, eluting with chloroform (3 x 200 mL) until the filtrates ran colorless. The combined filtrates were concentrated in vacuo to afford a yellow solid (64.5 g). The solid was broken up then triturated with MeCN (200 mL) via sonication and agitation, and the resulting fine yellow suspension filtered. The collected solids were washed with MeCN (2 x 100 mL) then vacuum dried on the sinter to constant weight, affording ethyl 2-(3-cyanophenyl)-3-(2,6-dimethyl-4- pyridyl)pyrazolo [l,5-a]pyrimidine-5- carboxylate (53.63g, 134.94mmol, 85% yield) as a pale yellow solid.

[0310] LC-MS: m / z 398.2 = [M+H]+

[0311] JH NMR (500 MHz, DMSO) 59.50 (d, J= 7.2 Hz, 1H), 8.11 (s, 1H), 8.06 (d, J= 7.8 Hz, 1H), 7.94 (d, J= 8.1 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.25 (s, 2H), 4.49 (q, J= 7.1 Hz, 2H), 2.50 (s, 6H), 1.46 (t, J= 7.1 Hz, 3H).

[0312] Step 7 - Ester hydrolysis

[0313] A solution of LiOH (3.56 g, 148.44mmol) in water (300mL) was added to a stirred partial suspension of ethyl 2-(3-cyanophenyl)-3-(2,6-dimethyl-4- pyridyl)pyrazolo [l,5-a]pyrimidine-5- carboxylate (53.63 g, 134.94mmol) in THF (900mL), after which the solids soon dissolved, and the resulting clear yellow-green solution stirred at room temperature for 45 mins, after which time UPLCMS analysis showed complete consumption of SM and formation of the DP as the sole UV active species. The mixture was diluted with water (1200 mL) and extracted with Et20 (3 x 1500 mL). To the resulting aqueous lithiate solution was added commercial IM analytical grade HC1 solution (147 mL) [resulting in a pH of ~ 5], followed by re-adjustment to pH 6 via addition of 10% aqueous NaOH (30 drops) resulting in the formation of a thick yellow precipitate. The suspension was stirred at room temperature for 15 mins before being filtered. The solids were washed with water (2 x 500 mL) and vacuum dried on the sinter overnight. The solids were then mechanically broken up, placed in a wide dish and dried to constant weight in a vacuum oven at 40 °C (alongside a tray of KOH flakes as desiccant) to afford 2-(3-cyanophenyl)-3- (2,6-dimethyl-4- pyridyl)pyrazolo[l,5-a] pyrimidine-5-carboxylic acid (49.77g, 134.74mmol, 99% yield) as a pale yellow solid.

[0314] LC-MS: m / z 370.2 = [M+H]+

[0315] 1H NMR (500 MHz, DMSO) 5 13.68 (br s, 1H), 9.37 (d, J= 7.2 Hz, 1H), 8.01 (s, 1H), 7.96 (d, J= 7.7 Hz, 1H), 7.84 (d, J= 7.9 Hz, 1H), 7.67 (apr t, J= 7.8 Hz, 1H), 7.65 (d, J= 7.2 Hz, 1H), 7.16 (s, 2H), 2.41 (s, 6H).

[0316] Step 8 - T3P amide coupling

[0317] A solution of DIPEA (187.75 mL, 1077.9mmol) in anhydrous THF (lOOOmL) was added to 2- (3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo [1,5- a]pyrimidine-5-carboxylic acid (49.77 g, 134.74mmol) under nitrogen, and the resulting mixture stirred until all of the solids had dissolved. (3S)-3-amino-2- methyl-butan-2-ol hydrochloride (28.22 g, 202.1 Immol) was then added and the mixture stirred for 5 mins to homogenise the suspended solids. A solution of T3P (50% in THF) (198.44 mL, 269.48mmol) was then added drop-wise via dropping funnel over 20 mins [NB - slight warming of the mixture, and the solids dissolved quickly once the T3P addition had begun. The mixture turned from clear to cloudy part way through the addition, then cleared again by the end of the addition]. The residues in the dropping funnel were washed into the reaction mixture with more anhydrous THF (lOmL), and the resulting mixture was stirred at room temperature for 45 mins, after which time basic UPLCMS analysis showed complete consumption of SM and formation of the DP as the sole UV active species. The mixture was diluted with EtOAc (500 mL) and water (500 mL), then agitated until all of the solids had dissolved. The layers were separated and the aqueous portion extracted with EtOAc (500 mL). The combined organic portions were washed with water (2 x 500 mL), brine (250 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford a yellow foam (64.8 g). This material was slurried and azeotroped with EtOAc then vacuum dried to afford crude 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)- N-[(lS)-2 -hydroxy-1 ,2- dimethyl- propyl]pyrazolo[l,5-a]pyrimidine-5-carboxamide (58 g, 127.61mmol, 95% yield) as a yellow solid.

[0318] LC-MS: m / z 455.3 = [M+H]+

[0319] JH NMR (500 MHz, DMSO) 59.41 (d, J= 7.1 Hz, 1H), 8.27 (d, J= 8.9 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J= 7.8 Hz, 1H), 7.91 (d, J= 7.9 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.21 (s, 2H), 4.77 (s, 1H), 3.90 - 3.82 (m, 1H), 2.40 (s, 6H), 1.19 (s, 3H), 1.18 - 1.14 (m, 6H).

[0320] Step 9 - Final recrystallisation

[0321] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(lS)-2-hydroxy-l,2-dimethyl- propyl]pyrazolo[l,5-a]pyrimidine-5-carboxamide (115.9 g, 254.99mmol) was dissolved in the minimum volume of refluxing MeCN (3150mL), then the flask left in the oil bath and the contents slowly allowed to cool to room temperature overnight. The suspension was filtered and the collected solids washed with chilled (5 °C) MeCN (2 x 200 mL), then vacuum dried on the sinter for Ih to afford large yellow crystals (112.8 g). UPLCMS analysis of this material showed 100% purity, and NMR analysis showed a clean product as well as ~ 7.1 wt% residual MeCN.

[0322] The crystallized solids were ground into a fine pale yellow powder with a mortar and pestle and dried in a vacuum oven at 55 °C until the MeCN was removed to afford the API, i.e., 2-(3-cyanophenyl)-3-(2,6- dimethyl-4-pyridyl)-N-[(lS)-2-hydroxy- 1,2- dimethyl-propyl]pyrazolo[l,5-a] pyrimidine-5- carboxamide (101.36g, 220.77mmol, 87% yield) as a pale yellow powder. The powder obtained was characterized by XRPD (FIG. 1) to be crystalline Form A. Form A (1.6% water) is a non-stoichiometric channel hydrate that shows a slightly different XRPD pattern as a function of its water content. The DSC, TGA, and H-NMR of Form A are shown in FIGs. 1-3. LC-MS: m / z 455.3 = [M+H]+

[0323] Chemical purity as determined: 99.3%

[0324] Enantiomeric excess as determined: > 9.9%

[0325] JH NMR (500 MHz, DMSO) 59.39 (d, J = 7.1 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 8.04 (s, 1H),7.98 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.70 (apr t, J = 7.8 Hz, 1H), 7.68 (d, J = 7.1Hz, 1H), 7.19 (s, 2H), 4.77 (s, 1H), 3.89 - 3.82 (m, 1H), 2.39 (s, 6H), 1.19 (s, 3H), 1.18 -1.13 (m, 6H).

[0326] 13C NMR (126 MHz, DMSO) 5 161.26 (C), 157.38 (2 x C), 152.47 (C), 150.28 (C), 144.71(C), 138.81 (C), 137.71 (CH), 133.57 (CH), 133.42 (C), 132.96 (CH), 132.07 (CH), 130.11 (CH), 119.71 (2 x CH), 118.31 (C), 111.94 (C), 107.07 (CH), 106.47 (C), 70.36 (C), 53.07 (CH), 27.07 (CH3), 26.56 (CH3), 24.04 (2 x CH3), 15.33 (CH3).

[0327] Example 2: Preparation of Form C

[0328] 300mg 2-(3-cyanophenyl)-3-(2,6- dimethyl-4-pyridyl)-N-[(lS)-2-hydroxy-l,2- dimethyl-propyl]pyrazolo[l,5-a] pyrimidine-5- carboxamide prepared according to Example 1 was weighed into an 8mL vial. 1.6mL EA was added into the vial under stirring at 50°C with 400rpm. About 5mg of Form C seeds obtained from Example 4g(l) (below) were added into the above suspension. The suspension was kept stirring at 50°C with 400rpm for 3 days. Solids were collected by centrifugation at 4,000 rpm for 5min and dried at ambient condition for 1 day. About 188mg of free form Form C was obtained as a yellow solid in 63% yield.

[0329] Example 3 : Preparation of F orm G

[0330] 200 mg 2-(3-cyanophenyl)-3-(2,6- dimethyl-4-pyridyl)-N-[(lS)-2-hydroxy-l,2- dimethyl-propyl]pyrazolo[l,5-a] pyrimidine-5- carboxamide prepared according to Example Iwas weighed into an 8mL vial. ImL acetone / water-1 / 1 was added into the vial under stirring at 25 °C with 400rpm. About 5mg of Form G seeds obtained from Example 4 (below) were added into the above suspension. The suspension was kept stirring at 25°C with 400rpm for 5 days. Solids were collected by centrifugation at 14,000 rpm for 5min. About 160mg of free form Form G was obtained as a yellow solid in 80% yield and dried at ambient condition for 1 day. Table 25 provides a summary of the characterization of this product.

[0331] Example 4: Preparation of Form G

[0332] About 1g of Example 1 was suspended in 4mL acetone / water (1 / 1 V / V) at 25°C.

[0333] The suspension was agitated at 25°C with 400rpm for 4 days. Solids were collected by centrifugation at 4,000 rpm for lOmin and dried at ambient condition for 1 day. About 970mg of free form Form G was obtained as a yellow solid in 97% yield.

[0334] Example 4(B): Preparation of Form B

[0335] 300mg of Pattern A, prepared according to Example 1 was weighed into a 20mL vial. lOmL MeOH was added into the vial under stirring at 50°C with 400rpm for lOmin. (suspension). The suspension was filtered by 0.45pm nylon filter. Obtained clear solution was put into a 0°C ice bath and agitated, (suspension). About 5mg of seeds from Product (1) of Table 11, prepared according to Example 13 (Pattern B seeds) were added into above suspension, (suspension) The suspension was kept stirring at 0°C with 400rpm for 3 days, (suspension). Solids were collected by centrifugation at 4,000 rpm for 5min and dried at ambient condition for 1 day. About 217mg of free form Pattern B was obtained as a yellow solid in 72% yield.

[0336] Polymorph Screening

[0337] A polymorph screen of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy-3-methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide was performed using the product from Example 1 as a starting material, or as otherwise specified in the following examples. The solid form landscape was investigated by equilibration, slow cooling, fast cooling, slow evaporation, fast evaporation and antisolvent addition experiments as described in Examples 5-26. Products from the screening experiments were investigated and characterized such as by XRPD, DSC, TGA, and 1H- NMR in accordance with standard procedures such as described herein. Example 5: Storage at Ambient Conditions

[0338] About 15mg of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2- prepared in accordance with Example 1 , was weighed into a 2mL glass vial. Different solvent or solvent mixture was added into the vial. Obtained mixture was stirred at 50°C for lOmin. Then the suspensions were filtered through a 0.45pm nylon membrane filter. Obtained clear solution was kept at ambient condition for 3 days.

[0339] Table 3

[0340] Example 6: Equilibration with solvents at 25° C for 9 days

[0341] 40 mg of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy- 3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide prepared in accordance with Example 1 was equilibrated in the solvent at 25 °C for 9 days with a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm. Obtained suspension was filtered through a 0.45pm nylon membrane filter by centrifugation at 14,000 rpm. Solid parts (wet cakes) were investigated and characterized

[0342] Table 4

[0343] Water activity calculated using UNIFAC method.

[0344] Example 7: Equilibration with solvents at 50° C for 6 days

[0345] 40 mg of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy- 3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide prepared in accordance with Example 1 was equilibrated in the solvent at 50°C for 6 days with a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm. Obtained suspension was filtered through a 0.45pm nylon membrane filter by centrifugation at 14,000 rpm. Solid parts (wet cakes) were investigated and characterized.

[0346] Table 5

[0347] Water activity calculated using UNIFAC method.

[0348] Example 8: Equilibration with Form S by solvents at 70°C for 5 days

[0349] 40mg of Form S was obtained from Form A (prepared in accordance with Example 1), which was then stored at ambient temperature for about 2 months. Form S was equilibrated in the solvent at 70°C for 5 days with a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm. Obtained suspensions were filtered through a 0.45pm nylon membrane filter by centrifugation at

[0350] 14,000 rpm for 5 min. Solid parts (wet cakes) were investigated by XRPD. Table 6

[0351] Example 9: Crystallization at room temperature by slow evaporation

[0352] 20mg of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide prepared in accordance with Example 1 was equilibrated in the solvent. Obtained suspensions were filtered through a 0.45 pm nylon membrane filter. Obtained clear solutions were slowly evaporated in ambient condition (about 20-25°C, 60-80%RH). Solid residues were investigated and characterized.

[0353] Table 7 Example 10: Crystallization at room temperature by fast evaporation

[0354] 20mg of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide prepared in accordance with Example 1 was equilibrated in the solvent. Obtained suspensions were filtered through a 0.45 pm nylon membrane filter. Obtained clear solutions were fast evaporated at ambient conditions (about 20-25°C, 60-80%RH) under a dry nitrogen flow. Solid residues were investigated and characterized.

[0355] Table 8

[0356] Example 11: Crystallization from hot saturated solutions by slow cooling

[0357] 40 mg of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy- 3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide prepared in accordance with Example 1 was dissolved in a minimal amount of selected solvents at 50°C. Obtained solutions were filtered through a 0.45 pm nylon membrane filter. Obtained clear solutions were cooled to 5 °C at 0.1 °C / min. Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000 rpm. Solid parts (wet cakes) were investigated and characterized.

[0358] Table 9

[0359] Example 12: Crystallization from hot saturated solutions by fast cooling

[0360] 40 mg of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy- 3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide prepared in accordance with Example 1 was dissolved in a minimal amount of selected solvents at 50°C. Obtained solutions were filtered through a 0.45 pm nylon membrane filter. Obtained clear solutions were put into a 0°C ice bath and agitated. Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000 rpm. Solid parts (wet cakes) were investigated and characterized.

[0361] Table 10

[0362] Example 13: Crystallization by addition of anti-solvent

[0363] 40 mg of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy- 3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide prepared in accordance with Example 1 was dissolved in the minimal amount of selected solvents at ambient temperature (about 20-25°C, 60-80%RH). 1-5 folds of anti-solvent was added into the obtained clear solutions slowly until solids precipitated out. Precipitates were collected by centrifugation filtration through a 0.45 pm nylon membrane filter at 14,000 rpm. Solid parts (wet cakes) were investigated.

[0364] Table 11

[0365] Example 14: Variable temperature XRPD (VT-XRPD) experiment

[0366] Product (1) of Table 11, prepared in accordance with Example 13, was used as starting material. One temperature cycle was applied. Initial XRPD analysis was carried out in ambient conditions. All the other XRPD analyses were carried out in nitrogen atmosphere at each specific temperature. Cycle 1: 25°C (initial)-80°C (lOmin) -25°C (lOmin). Table 12

[0367] Form B converted to Pattern M after heating to 80°C, and Pattern M converted back to Pattern B after cooling to 25°C. Pattern M is an unstable form at ambient conditions.

[0368] Example 15: Variable temperature XRPD (VT-XRPD) experiment

[0369] Product (2) of Table 5, prepared in accordance with Example 7, was used as starting material. One temperature cycle was applied. Initial XRPD analysis was carried out in ambient conditions. All the other XRPD analyses were carried out in nitrogen atmosphere at each specific temperature. Cycle 1: 25°C (initial)- 120°C (lOmin) -25°C (lOmin).

[0370] Table 13

[0371] Pattern D partially converted to Pattern B during storage at ambient condition for about 1 week.

[0372] Example 16: Variable temperature XRPD (VT-XRPD) experiment

[0373] Pattern C+E

[0374] Product (8) of Table 8 prepared in accordance with Example 10, was used as starting material. One temperature cycle was applied. Initial XRPD analysis was carried out in ambient conditions. All the other XRPD analyses were carried out in nitrogen atmosphere at each specific temperature. Cycle 1: 25°C (initial)- 150°C (lOmin) -25°C (lOmin).

[0375] Table 14

[0376] Pattern E partially converted to Pattern C during storage at ambient condition for about 10 days.

[0377] Example 17: Variable temperature XRPD (VT-XRPD) experiment

[0378] Product (1) of Table 5 prepared according to Example 7, was used as starting material. One temperature cycle was applied. Initial XRPD analysis was carried out in ambient conditions. All the other XRPD analyses were carried out in nitrogen atmosphere at each specific temperature. Cycle 1: 25°C (initial)-80°C (lOmin) -25°C (lOmin).

[0379] Table 15

[0380] Form G converted to Form N after heating to 80°C, and **Form N converted to Form G after exposure to ambient conditions for 9 days.

[0381] Example 18: Variable temperature XRPD (VT-XRPD) experiment

[0382] Pattern H,

[0383] Product (6) of Table 5, prepared according to Example 7, was used as starting material. One temperature cycle was applied. Initial XRPD analyses were carried out in ambient conditions. All the other XRPD analysis was carried out in nitrogen atmosphere at each specific temperature.

[0384] Cycle 1: 25°C (initial)- 100°C (10min)-150°C (10min)-25°C (lOmin).

[0385] Table 16

[0386] Pattern H converted to Pattern O after heating to 100°C. After heating to 150°C, the Pattern O converted to Pattern C, and it remains as Pattern C after cooling to 25°C.

[0387] Example 19: Variable temperature XRPD (VT-XRPD) experiment

[0388] Pattern I,

[0389] Product (2) of Table 9 prepared according to Example 11 , was used as starting material. One temperature cycle was applied. Initial XRPD analyses were carried out in ambient conditions. All the other XRPD analysis was carried out in nitrogen atmosphere at each specific temperature.

[0390] Cycle 1: 25°C (initial)- 125 °C (10min)-160°C (10min)-25°C (lOmin).

[0391] Table 17

[0392] Example 20: Competitive Equilibration Experiment

[0393] 5mg of 2-(3-cyanophenyI)-3-(2,6-dimethyIpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methyIbutan-2-yI]pyrazoIo[l,5-a]pyrimidine-5-carboxamide prepared in accordance with Example 1 and 5mg of Form C, prepared in accordance with Example 2, were added to 0.4 or 0.3mL saturated solutions of selected solvents. Obtained suspensions were stirred at 25°C and 50°C for 2 days. Solid parts (wet cakes) were isolated by centrifugation filtration and investigated by XRPD.

[0394] Table 18

[0395] The results show that Form C is more stable than Form A at both 25°C and 50°C.

[0396] Example 21: Water Activity Experiment

[0397] The water activity experiments were conducted at 25 °C in EtOH / water and EA / water systems to determine critical water activity between free form Form B, Form C and Form G. About 5mg of Pattern B prepared according to Example 4B, 5mg of Pattern C, prepared according to Example 2, and 5mg of Pattern G prepared according to Example 4, were added to 0.5mL saturated solutions of Ethanol / water and EA / water systems. Obtained suspensions were stirred at 25 °C for 1 week. Solid parts (wet cakes) were isolated by centrifugation filtration and investigated by XRPD.

[0398] Table 19 water activity is calculated by UNIFAC method.

[0399] Table 20 water activity is calculated by UNIFAC method.

[0400] Example 22: Stability Testing

[0401] Bulk stability of Form G (prepared according to Example 3) was evaluated at 25°C / 92%RH in an open container, at 40°C / 75%RH in an open container and at 60°C in a tight container for 1 week. Form G was chemically stable under these conditions, but it partially dehydrated at 60°C (Table 21).

[0402] Table 21. Bulk stability of Form G Bulk stability of Form C (prepared according to Example 2) was evaluated at 25°C / 92%RH in an open container, at 40°C / 75%RH in an open container and at 60°C in a tight container for 4 weeks. Form C was physically and chemically stable under these conditions (Table 22).

[0403] Table 22 - Bulk stability of Form C

[0404] Example 23: FTIR of Form C

[0405] The Infrared (IR) spectrum of Form C prepared in accordance with Example 2 is substantially similar to the one set forth in Figure 18 having weak peaks at about 3357cm" \ 2977 cm"1, 2932 cm"1, 2231 cm"1, 1585 cm"1, 860 cm"1, 833 cm"1.

[0406] Summary of Results from Examples 5-23

[0407] Form A:

[0408] Form A is a hygroscopic anhydrate. It was obtained from ACN and ACN / water mixture by equilibration experiments at 25°C. It is of high crystallinity. DSC shows a melting peak at Tonset of 120.2°C and a recrystallization peak at Tonset of 133.5°C. Then it melts at Tonset of 191.5°C with an enthalpy of about 75J / g. TGA shows about 0.3% weight loss at about 120.0°C. HPEC shows 98.2% chemical purity. 1HNMR shows no solvent residue. It is a metastable form. Competitive equilibration experiments show that the Form A converted to Form C in all of the selected solvents at 25°C and 50°C. After storage at ambient condition for about 2 months, Form A transitioned to a more hydrated variant Form S.

[0409] Form C:

[0410] Form C is a crystalline anhydrate. It was obtained from: • equilibration in ethanol (EtOH), acetone, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), ethyl acetate (EA), toluene, heptane;

[0411] • slow evaporation in acetone, MTBE, THF, isopropyl acetate (IPAc), EA;

[0412] • fast evaporation in EtOH, acetone, MTBE, THF, IPAc, EA;

[0413] • slow cooling in IPAc, EA;

[0414] • fast cooling in IPAc, EA; or

[0415] • anti-solvent experiments in EtOH / heptane, EA / heptane.

[0416] Form C prepared in accordance with Example 2 is a crystalline (FIG. 5) anhydrous form with a melting point of 192.6°C (FIG. 7) with an enthalpy of about 94 J / g. TGA shows about 0.5% weight loss at about 200.0°C. HPLC shows 99.6% chemical purity. 1H-NMR shows no solvent residue and is slightly hygroscopic (FIG. 8). Characterization of Form C is summarized in Table 23.

[0417] Table 23

[0418] Characterization of Form C

[0419] The crystal structure of Form C was solved at 25 °C in the monoclinic, space group P21 with the final Rl=[I>2s(I)] = 4.84 %. A summary of the structural data can be found in Table 23. The asymmetric unit contains two molecules of 2-(3-cyanophenyl)-3-(2,6- dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide (Table 24, FIG. 6).

[0420] Table 24. Single Crystal structure data of Form C measured at 25°C

[0421] Form C is a thermodynamically stable anhydrate at 15°C and at higher temperatures. Form C has an enantiotropic form that is stable at lower temperatures.

[0422] This low temperature enantiotropic form is Form Y. The SCXRD structures of Form C and Form Y were compared to produce an overlay of simulated XRD patterns of Form C and Form Y shown in Figure 37. SXRD, heat-cool-heat DSC and variable temperature XRD confirmed that there is an enaniotropic relationship between Form Y and Form C. Heat-cool-heat DSC analysis showed reversible enantiotropic transformation in the temperature range of 15-22 °C in all analysed batches. Variable temperature XRD confirmed that the transition temperature is between 5 and 15 °C.

[0423] Form G:

[0424] Form G of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy- 3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide was obtained from equilibration experiments in water, EtOH / water, or acetone / water.

[0425] Form G prepared in accordance with Example 3 is a crystalline (FIG. 9) dihydrate that desolvates upon heating (FIG. 10) and the resulting anhydrate (Form N) recrystallizes to Form C around 168°C (FIGs. 10 and 13). The sorption isotherm of Form G (FIG. 11) shows that Form G dehydrates below 30% RH, forming Form N, but its dehydration and rehydration is reversible, in agreement with the channel-like arrangement of water molecules in the lattice as seen in the crystal structure (FIG. 12, Table 24). The distinct, step-like sorption curves and hysteresis between the sorption and the desorption isotherms are indicative of a phase transformation (between Form N and Form G), typically observed for stoichiometric hydrates. Characterization of Form G is summarized in Table

[0426] Table 25

[0427] Characterization of Form G

[0428] Table 24. Single Crystal structure data of Form G measured at 100 K

[0429] Unit cell dimensions

[0430] The channel-hydrate nature and reversible dehydration / hydration is also evidenced by the VT-XRD results (FIG. 13, Table X?).

[0431] Form N:

[0432] Form N was an anhydrate and was obtained from heating Form G to 80°C by hot- stage XRPD. Form N is a metastable phase (Table 3) that converts to Form C upon heating (FIG. 14). The XRPD of Form N is shown in FIG. 15.

[0433] Table 25

[0434]

[0435] Table 26

[0436] Characterization of Polymorphs:

[0437] Weight Loss, Residual Solvent, Water Content Heating Study

[0438]

[0439]

[0440]

[0441] XRPD, DSC and TGA experiments described in the foregoing examples were conducted using the following parameters.

[0442] Example A

[0443] X-Ray Powder Diffraction

[0444] X-Ray powder diffraction patterns were collected on a Bruker D8 Advance using the following parameters:

[0445] Method (About 4 min)

[0446] Example B

[0447] Fourier Transform - Infra-Red (FTIR) Procedure

[0448] Data were collected on a Perkin-Elmer Spectrum One fitted with a universal Attenuated Total Reflectance (ATR) sampling accessory. The data were collected and analysed using

[0449] Spectrum v5. 0.1 software.

[0450] Example C

[0451] Differential Scanning Calorimetry (DSC) and Thermo- Gravimetric Analysis

[0452] TGA

[0453] DSC and TGA analyses were conducted using the following parameters:

[0454] Example D

[0455] Single Crystal X-Ray Diffraction (SCXRD)

[0456] Data were collected on a Rigaku Oxford Diffraction XtaLAB Synergy-S diffractometer equipped with a dualflex source (Cu at Zero), HyPix-6000HE detector or with a Rigaku Oxford Diffraction Supernova Dual Source, Cu at Zero, Atlas CCD diffractometer. Both instruments were equipped with an Oxford Cryosystems Cobra cooling device. The data were collected using Cu Ka radiation as stated in the experimental tables. Structures were solved and refined using the Bruker AXS SHELXTL suite or the 0LEX2 crystallographic software. Unless otherwise stated, hydrogen atoms attached to carbon were placed geometrically and allowed to refine with a riding isotropic displacement parameter. Hydrogen atoms attached to a heteroatom were located in a difference Fourier map and were allowed to refine freely with an isotropic displacement parameter. A reference diffractogram for the crystal structure was generated using Mercury (C. F. a. Macrae, “Mercury: visualization and analysis of crystal structures,” J. Appl. Cryst., vol. 39, pp. 453-457, 2006).

[0457] Example E

[0458] Polarised Light Microscopy (PLM)

[0459] Samples were studied on a Nikon SMZ1500 polarised light microscope with a digital video camera connected to a DS Camera control unit DS-L2 for image capture. The sample was viewed with appropriate magnification and partially polarised light, coupled to a I false-colour filter.

[0460] EXAMPLE F

[0461] Various Temperature X-Ray Powder Diffractometer (VT-XRPD)

[0462] X-Ray powder diffraction patterns were collected on a Bruker D8 Advance using the following parameters:

[0463] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present inventions as defined by the specific description.

Claims

Claims:

1. A crystalline form A of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5- carboxamide that is characterized as having at least one of:(i) an X-ray powder diffraction pattern comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 1 ;(j) an X-ray diffraction pattern with characteristic peaks at 6.03+0.1° 20, 8.22+0.1 °20, 12.04+0.1 °20, 13.11+0.1 °20, 16.73+0.1 °20, 17.63 +0.1 °20, 18.75 +0.1 °20, 24.14 +0.1 °20, 25.10 +0.1 °20 and 27.61 +0.1 °20;(k) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting peak at TonSet of about 120.2°C and a recrystallization peak at TonSetof about, 133.5°C, and a melting peak at TonSet of about 191.5°C with an enthalpy of about 75 J / g;(l) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C, preferably from 190°C to 195°C, and more preferably about193.6°C;(m) a differential scanning calorimetry curve substantially similar to FIG. 2;(n) a thermogravimetric analysis curve substantially similar to FIG. 3;(o) a thermogravimetric analysis curve shows about 0.3% weight loss at about 120.0°C;(p) or combinations thereof.

2. The crystalline Form A according to Claim 1 wherein Form A is substantially free of Form S.

3. A crystalline form S of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5- carboxamide that is characterized as having at least one of:(e) an X-ray powder diffraction pattern having substantially the same peaks at diffraction angles (20) as shown in FIG. 31 A;(f) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a dehydration peak at Tonset of 14.3°C with an enthalpy of about 33J / g, and a melting peak at Tonset of 120.6°C and arecrystallization peak at Tonset of 133.1°C. Then it melts at Tonset of 190.9°C with an enthalpy of about 80J / g;(g) a differential scanning calorimetry curve substantially similar to FIG. 3 IB;(h) or combinations thereof.

4. A crystalline form C of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5- carboxamide that is characterized as having at least one of:(m)an X-ray powder diffraction pattern comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 5;(n) an X-ray diffraction pattern with characteristic peaks at 3.12+0.1° 20, 6.19+0.1 °20, 9.26+0.1 °20, 12.35 +0.1 °20, 13.28+0.1 °20, 14.16 +0.1 °20 , 15.44 +0.1 °20 , 16.40 +0.1 °20 , 17.71 +0.1 °20 and 18.55 +0.1 °20;(o) unit cell dimensions comprising a— 11.25010(2) A, b=7.56347(13)A, C~28.864I(3) , aipha:::90 deg., beta::::94.6337(11) deg., gamma:::90 deg;(p) unit cell dimensions substantially similar to those in Table 23;(q) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting peak at TonSet of about 191.2°C with an enthalpy of about 71 J / g;(r) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C, preferably from 190°C to 195°C, and more preferably about192.6°C;(s) a differential scanning calorimetry curve is substantially similar to the differential scanning calorimetry curve in FIG. 7B ;(t) a thermogravimetric analysis curve, wherein the thermogravimetric analysis curve is substantially similar to the thermogravimetric analysis curve in FIG. 7A;(u) thermogravimetric analysis curve shows about 0.6% weight loss at about 200.0°C;(v) or combinations thereof.

5. The crystalline Form C according to Claim 4 wherein Form C has substantially the same X-ray diffraction (XRPD) pattern post storage at 40°C and 75% RH for at least 4 weeks.

6. The crystalline Form C according to Claim 4 wherein Form C has substantially the same X-ray diffraction (XRPD) pattern post storage at 25 °C and 92% RH for at least 4 weeks.

7. A crystalline form G of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5- carboxamide that is characterized as having at least one of:(m)an X-ray powder diffraction pattern comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 9;(n) an X-ray diffraction pattern with characteristic peaks at 5.55 ±0.1° 20, 8.22 ±0.1 °20, 9.49 ±0.1 °20, 12.53 ±0.1 °20, 13.41 ±0.1 °20, 13.53 ±0.1 °20 , 14.46 ±0.1 °20 , 14.72 ±0.1 °20 , 15.48 ±0.1 °20, 16.65 ±0.1 °20 , 17.57 ±0.1 °20, 18.24 ±0.1 °20, 18.50 ±0.1 °20, 20.07 ±0.1 °20 , 20.51 ±0.1 °20, 21.44 ±0.1 °20, 22.68 ±0.1 °20, 24.52 ±0.1 °20, and 25.90 ±0.1 °20.(o) unit cell dimensions comprising a~7.1582(2) A, b=l 1.3672(3)A, c~32.0153(7)A, aipha:::90 deg., beta::::90 deg., gamma:::9() deg;(p) unit cell dimensions that are substantially similar to those in Table 2;(q) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a dehydration peak at TonSet of 33.3°C with an enthalpy of about 206 J / g and an exothermic peak at TonSet of 168.1°C with an enthalpy of about 23 J / g, and an endothermic peak at TonSetof 193.7°C with an enthalpy of about 76 J / g;(r) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C;(s) a differential scanning calorimetry curve is substantially similar to the differential scanning calorimetry curve in FIG. 10A;(t) a thermogravimetric analysis curve that is substantially similar to the thermogravimetric analysis curve in FIG. 10B;(u) a thermogravimetric analysis curve that shows about 6.2% weight loss at about 65 °C; or(v) combinations thereof.

8. The crystalline Form G according to Claim 7 wherein Form G has substantially the same X-ray diffraction (XRPD) pattern post storage at 40°C and 75% RH for at least 4 weeks.

9. The crystalline Form G according to Claim 7 wherein Form G has substantially the same X-ray diffraction (XRPD) pattern post storage at at 25°C and 92% RH for at least 4 weeks.

10. A crystalline form N of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5- carboxamide that is characterized as having at least one of:(g) an X-ray powder diffraction pattern comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 15;(h) an X-ray diffraction pattern with characteristic peaks at 5.44 ±0.1° 20, at 6.05 ±0.1° 20, at 8.52 ±0.1° 20, at 13.29 ±0.1° 20, at 14.85 ±0.1° 20, at 16.40 ±0.1° 20, at 16.76 ±0.1° 20, at 18.23 ±0.1° 20, at 24.43 ±0.1° 20, and at 24.95 ±0.1° 20;(i) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises an exothermic peak at TonSet of 164.1 °C with an enthalpy of about 23 J / g and an endothermic peak at TonSet of 193.8°C with an enthalpy of about 83 J / g;(j) a differential scanning calorimetry curve, wherein the differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C;(k) a differential scanning calorimetry curve which is substantially similar to FIG. 14;(l) or combinations thereof.

11. A crystalline form of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5- carboxamide that is characterized as having:(a) an X-ray powder diffraction pattern A comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 1 ;(b) an X-ray powder diffraction pattern B comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 17A;(c) an X-ray powder diffraction pattern C comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 5;(d) an X-ray powder diffraction pattern D comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 18 A;(e) an X-ray powder diffraction pattern E comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 19A;(f) an X-ray powder diffraction pattern F comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 20A;(g) an X-ray powder diffraction pattern G comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 9;(h)(i) an X-ray powder diffraction pattern H comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 21A;(j) an X-ray powder diffraction pattern I comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 22A;(k) an X-ray powder diffraction pattern J comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 23A;(l) an X-ray powder diffraction pattern K comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 24A;(m)an X-ray powder diffraction pattern L comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 25A;(n) an X-ray powder diffraction pattern M comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 26;(o) an X-ray powder diffraction pattern O comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 27 ;(p) an X-ray powder diffraction pattern P comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 28;(q) an X-ray powder diffraction pattern Q comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 29A;(r) an X-ray powder diffraction pattern R comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 30A;(s) an X-ray powder diffraction pattern S comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 31A;(t) an X-ray powder diffraction pattern T comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 32A;(u) an X-ray powder diffraction pattern U comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 33A;(v) an X-ray powder diffraction pattern V comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 34A;(w) an X-ray powder diffraction pattern W comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 35A;(x) an X-ray powder diffraction pattern X comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 36A; or(y) an X-ray powder diffraction pattern Y comprising substantially the same peaks at diffraction angles (20) as shown in FIG. 37 ; and(z) combinations thereof.

12. A crystalline form of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3 - hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5- carboxamide of any one of (a) - (t) of Claim 11 that is substantially pure.

13. A method of preparing crystalline Form C according to claim 4 comprising(a) suspending 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide in ethyl acetate to form a suspension, optionally adding a Form C seed, and stirring the suspension at a suitable temperature for a suitable period of time to obtain crystalline Form C; or(b) dissolving 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide in 2-methyltetrahydrofuran to form a solution under heating, cooling the solution to a suitable temperature, adding heptane, and obtaining crystalline Form C.

14. A method of preparing crystalline Form G according to Claim 7, comprising suspending 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide in a mixture of acetone and water to form a suspension, optionally adding a Form G seed, and stirring the suspension at a suitable temperature for a suitable period of time to obtain crystalline Form G.

15. A pharmaceutical composition comprising an effective amount of a crystalline form of Claim 11, and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising an effective amount of a crystalline form of Claim 12, and a pharmaceutically acceptable carrier.

17. A method for treating a disease or disorder in which A2a is implicated, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 15.

18. A method for treating a disease or disorder in which A2a is implicated, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 16.

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